Knockdown of the Potential Cancer Stem-Like Cell Marker Rex-1 Improves Chemotherapeutic Effects in Gliomas

In the present study, we show that Rex-1 mRNA and protein are found at high levels in both 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)-resistant glioma cell subpopulations and malignant glioblastoma multiforme (GBM) tissue. We used a combination therapy of small interfering RNA (siRNA) against Rex-1 (siRex-1) and BCNU to target GBM cells. Rex-1 siRNA/BCNU treatment resulted in growth inhibition and a diminished S phase. The treatment efficiently induced P38/JNK and Akt/PI3K/GSK3 beta signaling and led to apoptosis both in vitro and in vivo. We also show that Rex-1/ABCG2 (ATP binding cassette transporter G2)-coexpressing subpopulations were chemoresistant; however, BCNU was not a substrate for ABCG2. siRex-1 treatment led to cell death in GBM subpopulations by promoting apoptosis. Moreover, siRex-1/BCNU combination therapy targeted both the major population and cancer stem cell-like subpopulations. Our findings are important for the development of clinical applications to treat GBM.